Phase II Trial of Bevacizumab and Irinotecan in Recurrent Malignant Glioma

Abstract

Purpose: Recurrent grade III-IV gliomas have a dismal prognosis with minimal improvements in survival seen following currently available salvage therapy. This study was conducted to determine if the combination of a novel antiangiogenic therapy, bevacizumab, and a cytotoxic agent, irinotecan, is safe and effective for patients with recurrent grade III-IV glioma. Experimental Design: We conducted a phase II trial of bevacizumab and irinotecan in adults with recurrent grade III-IV glioma. Patients with evidence of intracranial hemorrhage on initial brain magnetic resonance imaging were excluded. Patients were scheduled to receive bevacizumab and irinotecan i.v. every 2 weeks of a 6-week cycle. Bevacizumab was administered at 10 mg/kg. The dose of irinotecan was determined based on antiepileptic use: patients taking enzyme-inducing antiepileptic drugs received 340 mg/m 2 , whereas patients not taking enzymeinducing antiepileptic drugs received 125 mg/m 2 . Toxicity and response were assessed. Results:Thirty-two patients were assessed (23 with grade IV glioma and 9 with grade III glioma). Radiographic responses were noted in 63% (20 of 32) of patients (14 of 23 grade IV patients and 6 of 9 grade III patients).The median progression-free survival was 23 weeks for all patients (95% confidence interval, 15-30 weeks; 20 weeks for grade IV patients and 30 weeks for grade III patients). The 6-month progression-free survival probability was 38% and the 6-month overall survival probability was 72%. No central nervous system hemorrhages occurred, but three patients developed deep venous thromboses or pulmonary emboli, and one patient had an arterial ischemic stroke. Conclusions: The combination of bevacizumab and irinotecan is an active regimen for recurrent grade III-IV glioma with acceptable toxicity.

ACNU-based chemotherapy for recurrent glioma in the temozolomide era

“…Thus, the relatively poor results in this study could be due to the fact that the combination partners in the PBV and PCV regimens contribute to this efficacy or that temozolomide pre-treated patients are less likely to respond to nitrosoureas at recurrence. Altogether, treatment results with ACNU are inferior compared with the recent studies with bevacizumab/irinotecan [18,19] or doseintensified temozolomide [17] and also showed considerable hematotoxicity. We do not propose that our data exclude a role of ACNU in certain subgroups of patients or within combined treatments in recurrent glioblastoma.…”

“…In the latter study, patients who had received temozolomide as a first-line therapy benefited from a dose-intensified re-exposure, too. Another phase II study evaluated the use of bevacizumab, a monoclonal antibody to vascular endothelial growth factor, in combination with irinotecan, a topoisomerase inhibitor [18,19]. This study reached a PFS-6 of 46% in patients with recurrent glioblastoma.…”

Therapeutic options in recurrent glioblastoma—An update

“…However, no direct comparisons are available and the trials evaluating bevacizumab plus temozolomide were conducted in part in highly pretreated patient populations [72][73][74]. Five phase II trials evaluated the combination of irinotecan with bevacizumab [91][92][93][94][95], two trials added a third combination partner, cetuximab [96] or carboplatin [97]. PFS-6 rates ranged between 28 and 50.3% and median OS between 6.7 and 9.7 months.…”

Bevacizumab and glioblastoma: Scientific review, newly reported updates, and ongoing controversies

“…A prospective phase 2 study using every-3-week dosing of bevacizumab at a dose of 15 mg/kg in 61 patients with World Health Organization grade 3 or grade 4 glioma demonstrated no obvious differences in patient outcomes compared with contemporary studies using every-2-week dosing at 10 mg/kg, 37 thus allowing for flexibility in patient scheduling without clinical detriment. Several phase 2 trials of bevacizumab-based combinations have also been reported for recurrent glioblastoma (Table 1), 27,28,32, including bevacizumab with irinotecan, irinotecan plus cetuximab, irinotecan plus carboplatin, etoposide, fotemustine, sorafenib, temozolomide, erlotinib, and temsirolimus. 27,28,32,[38][39][40][41][42][43][44][45][46][47] In addition, several retrospective studies have also been reported combining bevacizumab and irinotecan; carboplatin; carboplatin and cetuximab; carboplatin, etoposide, and ifosfamide; lomustine; carmustine; etoposide; or temozolomide.…”

“…Several phase 2 trials of bevacizumab-based combinations have also been reported for recurrent glioblastoma (Table 1), 27,28,32, including bevacizumab with irinotecan, irinotecan plus cetuximab, irinotecan plus carboplatin, etoposide, fotemustine, sorafenib, temozolomide, erlotinib, and temsirolimus. 27,28,32,[38][39][40][41][42][43][44][45][46][47] In addition, several retrospective studies have also been reported combining bevacizumab and irinotecan; carboplatin; carboplatin and cetuximab; carboplatin, etoposide, and ifosfamide; lomustine; carmustine; etoposide; or temozolomide. [48][49][50][51][52][53][54][55][56][57][58] Although these small studies are not easily compared due to their size and various patient populations, the consensus to date has been that no combination significantly surpasses the outcomes of bevacizumab monotherapy for recurrent glioma.…”